Multiple emulsions

ABSTRACT

A multiple emulsion to administer at least one water-soluble or liposoluble active ingredient in the form of a water/oil/water emulsion comprising a dispersed phase of a water/oil type and an aqueous dispersion medium which is a gelled aqueous phase useful as cosmetic compositions for external skin application.

STATE OF THE ART

French patent no. 2,326,914 describes a multiple emulsion of thewater/oil/water type containing a dispersed phase and a dispersingmedium wherein the dispersed phase is an emulsion containing a waterphase and an oil phase containing dissolved therein an oil solubleemulsifier and the dispersion medium is an aqueous solution containing awater-soluble emulsifier. Each phase contained an emulsifier and thereoften is an interaction between the said emulsifiers required for theprimary emulsion and the secondary emulsion. This can result in alimited selection, uncertain stabilities due to phase inversion,transition to a single emulsion or a phase shift and therefore anaverage cosmetic quality.

OBJECTS OF THE INVENTION

It is an object of the invention to provide an improved multipleemulsion for water-soluble or liposoluble active ingredients andcosmetic compositions produced therefrom.

These and other objects and advantages of the invention will becomeobvious from the following description.

THE INVENTION

The novel multiple emulsions of the invention to administer at least onewater-soluble or liposoluble active ingredient in the form of awater/oil/water emulsion are comprised of a dispersed phase of awater/oil type and an aqueous dispersion medium which is a gelledaqueous phase.

The primary water/oil emulsion is a standard type with surfactantsusually used in cosmetics for this type of emulsion. However, thisprimary emulsion is then dispersed in an aqueous phase gelled withgelling agents which replace the emulsifiers. The primary emulsiondroplets are immobilized by the flexible gel system and therefore theycannot coalesce, resulting in very high stability.

As there is no emulsifier in the external aqueous phase, the primaryemulsion is not disturbed by a diffusion of emulsifiers. Altogether, astable, multiple emulsion is obtained, produced with cosmetic rawmaterials which allows it to be quite harmless and agreeable to thetouch.

The present invention also relates to the incorporation of water-solubleor liposoluble active ingredients in such a multiple emulsion.

The desired aims of such a multiple emulsion of the invention are toseparate incompatible water-soluble active ingredients by incorporatingthem in two aqueous phases separated by an oily phase, which allowsparticular cosmetic compositions to be prepared which can progressivelyrelease the active ingredients over the skin because the structures ofthe multiple emulsion are destroyed more slowly than those of a singleemulsion. Thus, there is an increase of the penetration of activeingredients because the internal structure of multiple emulsions andnotably triple emulsions is, in some cases, similar to certainstructures which act as a barrier for the skin.

A preferred multiple emulsion as described above is characterized inthat the gelling agent or agents contained in the aqueous dispersionphase are selected from the group consisting of a solution based onpolyglyceryl methacrylate, xanthan gum, polysaccharides, carbomers,modified carbomers, hydroxy ethyl cellulose and modified hydroxy ethylcellulose.

A preferred multiple emulsion of the invention is characterized in thatthe gelling agent contained in the aqueous dispersion phase is a mixtureof a solution based on polyglyceryl methacrylate, carbomers and modifiedcarbomers. The solution based on polyglyceryl methacrylate can beLubragel® and the modified carbomers can be Pemulen® TR1 and TR2.

Examples of such gelling agents used alone or in mixtures are used inthe following preferred percentages expressed relative to the finalcomplete formula: Lubragel®: 1 to 30%, Xanthan gum: 0.05 to 2%,Polysaccharide Amigel®: 0.05 to 2%, Carbomers: 0.01 to 2%, Modifiedcarbomers (Pemulen®TR1 and TR2): 0.04 to 2% or Hydroxy ethyl celluloseand modified hydroxy ethyl cellulose (Amercell®): 0.05 to 3%.

Among the preferred gelling agents of the invention is the mixture of 5to 15% by weight of LUBRAGEL®, 0.05 to 0.3% by weight of carbomers and0.1 to 0.8% by weight of modified carbomers.

A particular subject of the present invention is a multiple emulsion, asdescribed above, characterized in that one or more water-soluble activeingredients are incorporated in the aqueous phase of the water/oilemulsion and/or in the aqueous dispersion phase or a multiple emulsionwith one or more liposoluble active ingredients incorporated in the oilyphase of the water/oil emulsion.

A preferred multiple emulsion is characterized in that the water-solubleactive ingredients are selected from the group consisting of sodiumlactate, hafnia biolysate extracts, Klebsiella pneumonia biolysateextracts and water-soluble sun filters.

Examples of preferred water-soluble sun filters are neutralized 2-phenylbenzimidazol-5-sulfonic acid, neutralized2-hydroxy-4-methoxybenzophenone-5-sulfonic acid, ascorbic acid, caffeinebenzoate, phytic acid, mucic acid, vegetable protein hydrolysates,polygulcan, Mexican mimosa extract, chitosan, marine animal serum,hirudin extract, meristem extract, procyanodolic oligomers, yeastextracts, panthenol, centella asiatica extract and glycyrrhetinic acid.

Examples of suitable amount of water-soluble active ingredients areexpressed relative to the weight of the final complete formula,neutralized 2-phenyl-benzimidazol-5-sulfonic acid: 0.5 to 8%,neutralized 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid: 0.5 to 5%,Ascorbic acid: 0.5 to 10%, caffeine benzoate: phytic acid: 0.1 to 5%,mucic acid: 0.1 to 5%, 0.1 to 5%, vegetable protein hydrolysates: 0.1 to10%, polyglucan: 0.1 to 5%, Mexican mimosa extract: 0.5 to 20%,chitosan: 0.5 to 20%, marine animal serum: 0.1 to 3%, hirudin extract:0.5 to 10%, meristem extract: 0.1 to 5%, procyanodolic oligomers; 0.05to 3%, yeast extracts: 0.05 to 3%, panthenol: 0.05 to 5%, centellaasiatica extract: 0.05 to 3% or glycyrrhetinic acid: 0.05 to 2%.

Examples of liposoluble active ingredients are the palmitate of vitaminA, liposoluble sun filters, non-saponifiable matter of vegetable origin,vegetable oils, tocopherol acetate, natural tocopherols, farnesol,natural or synthetic ceramides.

Examples of liposoluble solar filters are octyl methoxycinnamate,isoamyl methoxycinnamate, octyl dimethyl paba, octyl salicylate, butylmethoxydibenzoyl methane, benzophenone-3, octyl triazone, ethyl4-polyethoxy aminobenzoate and isopropyl 4-dibenzoyl methane.

The non-saponifiable matter of vegetable origin can be chosen fromnon-saponifiable matter of corn, karite, soya and avocado. The vegetableoils can be peroxidated or not and may be chosen from an oily mixturecontaining xymenic acid, essential extract of sesame oil, peroxidatedcorn oil, evening primrose oil, peroxidated evening primrose oil, borageoil and peroxidated borage oil. The oily mixture containing xymenic acidcan be Xymenoil® which contains 50% of this acid.

Examples of such liposoluble active ingredients are, expressed relativeto the weight of the final complete formula, Palmitate of vitamin A: 500to 10,000 UI/g. Liposoluble solar filters: octyl methoxycinnamate: 0.5to 10%, isoamyl methoxycinnamate: 0.5 to 10% octyl dimethyl paba: 0.50to 8%, octyl salicylate: 0.5 to 5%, butyl methoxydibenzoyl methane: 0.5to 5%, benxophenone-3: 0.5 to 10%, octyl triazone: 0.5 to 5%, ethyl4-polyethoxy amino-benzoate: 0.5 to 10%, isopropyl-4-dibenzoyl methane:0.5 to 5%, Non-saponifiable matter of corn, karite, soya or avocado: 0.1to 3%,, Xymenoil®: 0.1 to 5%, essential extract of sesame oil: 0.1 to4%, peroxidated corn oil: 0.1 to 10%, evening primrose oil: 0.1 to 10%,peroxidated evening primrose oil: 0.1 to 10%, borage oil: 0.1 to 10%,peroxidated borage oil: 0.1 to 10%, tocopherol acetate: 0.05 to 7%,natural tocopherols: 0.05 to 5%, farnesol: 0.05 to 5% and natural orsynthetic ceramides: 0.01 to 10%.

Preferably, a multiple emulsion is characterized in that the volumes ofthe different phases are such that: the internal aqueous phase is 20 to30% of the total composition, the oily phase is 10 to 20% of the totalcomposition, and the external aqueous phase is 50 to 60% of the totalcomposition.

The process for the preparation of a multiple emulsion of the inventioncomprises strongly stirring an aqueous phase and an oil phase to form adispersed phase and gently stirring said dispersed phase with a gelledaqueous phase free of emulsifier to form a multiple emulsion.

Preferably, the dispersed phase is heated during the strong stirring andthe gentle stirring is effected at room temperature. More preferably,the primary emulsion is produced by introducing the aqueous phase heatedto 80° C. into the oily phase also at 80° C. under vigorous stirring.The second stage consists of mixing the primary emulsion and the gelledexternal aqueous phase at ordinary temperature under mild stirring untilformation of the multiple emulsion.

A preferred multiple emulsion is characterized in that the gelling agentused to prepare the external aqueous phase is selected from the groupconsisting of a solution based on polyglyceryl methacrylate, xanthangum, polysaccharides, carbomers, modified carbomers, hydroxy ethylcellulose and modified hydroxy ethyl cellulose.

The cosmetic compositions of the invention are comprised of a multipleemulsion of the invention containing a cosmetically effective amount ofa water-soluble or liposoluble active ingredient.

Examples of the excipients of the oily phase are vegetable oils such asjojoba, olive, avocado, macadamia oils, mineral oils such as oils ofvaseline, hydrocarbons such as dioctyl cyclohexane or isohexadecane,esters such as ketyl palmitate or isoketyl isostearate, natural waxessuch as beeswax, carnauba wax, candellila wax, semi-synthetictriglycerides such as caprylic or capric triglycerides, fatty alcoholssuch as ketylic or stearylic alcohol, propylene glycol esters such aspropylene glycol monostearate.

Examples of other additives are antiseptics, preservatives such asparabens, bronopol, biosol, wetting agents such as glycerine, propyleneglycol, sorbitol, polyoxyethylene glycol 400, as well as coloring agentsin the aqueous phase.

The cosmetic compositions of the invention can be presented in all theforms used in dermatology, more particularly those which areadministered by topical route. The cosmetic compositions can bepresented as standard skin care products such as in the form ofmoisturizing creams, total-screen creams, day creams, night creams,masks or as make-up products such as foundation cream and tinted cream,or as make-up removal products or also as hygiene products.

Such compositions can be in liquid or paste form such as creams:moisturizing creams, day creams, night creams, ointments, masks, make-upcreams, milks, as well as lotions and particularly sun lotions.

Such compositions may be packaged according to the case, in pots or intubes, in glass or plastic bottles or optionally in dropping bottles oralso in vials and are prepared according to the usual methods.

Preferably, a cosmetic composition is characterized in that it containsa multiple emulsion and optionally one or more usual excipients includedin the multiple emulsion, as well as one or more suitable activeingredients. More preferred as a particular subject of the presentinvention is a cosmetic composition in the form of a sun lotion.

The invention also relates to new cosmetic compositions intended fortreating blackheads characterized in that it contains a multipleemulsion and optionally one or more usual excipients as well as one ormore suitable active ingredients.

The cosmetic compositions may also be to treat spotty skin, dehydratedskin, injured skin, wrinkled skin and are characterized in that theycontain a multiple emulsion and optionally one or more usual excipients,as well as one or more suitable active ingredients.

In the following examples, there are described several preferredembodiments to illustrate the invention. However, it is to be understoodthat the invention is not intended to be limited to the specificembodiments.

EXAMPLE 1

A) A primary water/oil emulsion was prepared in the following manner:The following aqueous phase, called the internal aqueous phase, washeated to 80° C.:

    ______________________________________                                        demineralized water    26.52 g                                                methylparaben          0.1 g                                                  magnesium sulfate      0.28 g                                                 glycerine 30° Be                                                                              0.8 g                                                  0-cymen-5-ol           0.04 g                                                 ______________________________________                                    

The following oily phase was also heated separately to 80° C.:

    ______________________________________                                        glyceryl isostearate      2.0 g                                               polyethoxylated hydrogenated ricin oil                                                                  0.2 g                                               (7 moles)                                                                     capric/caprylic triglycerides                                                                           8.2 g                                               propylparaben             0.06 g                                              volatile silicone oil     1.6 g                                               ______________________________________                                    

The aqueous phase was dispersed into the oily phase at 80° C. bystirring vigorously for 5 minutes and then the mixture was slowly cooleddown to 25° C.

B) The multiple emulsion was prepared in the following manner:

The primary emulsion obtained in a) was then dispersed in the followingaqueous phase, called the external aqueous phase, by mixing gently atambient temperature:

    ______________________________________                                        demineralized water  s.q.f. 100.0 g                                           Lubragel MS ®    15.0 g                                                   Pemulen TR1 ®    0.6 g                                                    Carbopol 980 ®   0.03 g                                                   tetrasodium EDTA     0.054 g                                                  methylparaben        0.216 g                                                  imidazolidinyl urea  0.216 g                                                  pure soda            0.125 g                                                  perfume              0.2 g                                                    ______________________________________                                    

Characterization by Rheological Study

The rheological study was carried out using a CSL 100 viscometer withimposed stress (RHE0, 91 Champlan) at 25°±1° C. The geometry of theshearing action used was a cone/plate geometry (diameter=4 cm, coneangle=2°) and allowed analyses by sweeping under stress from 0.6 Pa to600 Pa to be carried out. The displacement sensor had a resolution of10⁻⁵ rd and the results were analyzed with Carri50 software. Two typesof studies were carried out:

1--Oscillatory viscoelastic analysis (dynamic)

This analysis was carried out in such a way as to provide a very preciseand characteristic signature of the "at rest" structure of the examples.In this type of analysis, the sample was subjected to a pulsedsinusoidal shearing action=2N (N: frequency of shearing action), whichwas defined by the following expressions of shear stress anddeformation.

shear stress τ (t)=₀ cos t

shear deformation ε (t)=ε_(o) cos(wt+δ)

These experiments allowed a certain number of rheological variablescharacteristic of the sample to be defined.

shear modulus G*=τ₀ /ε₀

phase shift (stress/deformation) δ

loss modulus G"=G*sin δ

During this experiment, sweeping under stress at a fixed frequency wascarried out during which the evolution of G*, δ, G" was recorded. Aplateau area characteristic of a non-modified structure (structure atrest) was obtained for values of the stress which were lower than acertain critical value (τ₀)_(c) or the stress for which G" represents amaximum.

The dynamic rheological variables retained as characteristic sizes ofthe structure were:

the average value of G* calculated at the level of the plateau- theaverage of δ calculated at the level of the plateau,

the value of the critical stress (τ₀)_(c)

the value of the critical deformation (ε₀)_(c).

The values indicated in the table below were obtained for the multipleemulsion of Example 1.

    ______________________________________                                               G* (Pa)                                                                              155                                                                    δ (deg)                                                                        10                                                                     τc (Pa)                                                                          72                                                                     εc                                                                           0.78                                                            ______________________________________                                    

2--Permanent flow system analysis

This type of test was intended to provide information on the role of theshearing action in an optional destructuring and on its more or lessreversible character. This experiment was carried out under shearingconditions which reproduced those which would be optionally implementedduring use on the skin (maximal shearing speed ε max=10³ S⁻¹). For thistype of analysis, permanent flow tests were carried out during which thesample will be sheared according to successively increasing stresscycles (rise), constant stress cycles (plateau) and decreasing stresscycles (descent).

This succession of stress cycles was used on a sample according to theprotocol:

a) shearing cycle on a "new" sample having undergone no pre-shearingaction,

b) shearing cycle on the same sample after leaving at rest for one hour,

c) shearing cycle on the same sample after a one hour pre-shearingaction at a speed of 10³ S⁻¹.

The quantitative treatment of the rheogram was carried out by lookingfor the best adjustment which was usually provided by the CROSS model.This permanent flow system analysis was completed by oscillatoryrheological analyses which had been carried out on the same sample,before or after each shearing cycle. More precisely, four sweeps understress at a fixed frequency and temperature (N=1 Hz, t=20° C.) werecarried out according to the following sequence:

a': on the "new" sample, before cycle a,

b': immediately after cycle a,

c': immediately after cycle b,

d': immediately after cycle c.

For the product of the multiple emulsion of Example 1, the results ofoscillatory rheological analyses (rings a', b', c' and d') which werecarried out on the same sample before and after each shearing cycle(rings a, b, c) and the average values of G* indicated in the tablebelow were obtained:

    ______________________________________                                               Sweep         G* (Pa)                                                         Cycle a'      133                                                             Cycle b'      111                                                             Cycle c'      105                                                             Cycle d'      117                                                      ______________________________________                                    

CONCLUSION

A relative variation of G* was observed which was very low and ofsimilar size to the relative variations of the parameters of Cross'slaw. The shearing action exerted a quite negligible influence on thesamples (during the interval of time the stresses were used). This wasdue to a useful property related to the stability of the multipleemulsion obtained in Example 1.

EXAMPLE 2

A) A primary water/oil emulsion was prepared in the following manner:

The following aqueous phase called the internal aqueous phase was heatedto 80° C.:

    ______________________________________                                        demineralized water       26.52 g                                             methylparaben             0.1 g                                               magnesium sulfate         0.28 g                                              glycerine 30° B    0.8 g                                               0-cymen-5-ol              0.04 g                                              The following oily phase was heated                                           separately to 80° C.:                                                  gylceryl isostearate      2.0 g                                               PEG-7 hydrogenated Castor Oil                                                                           0.2 g                                               capric/caprylic triglycerides                                                                           8.2 g                                               propylparaben             0.06 g                                              mineral oil/quaternium 18 hectorite/                                                                    0.2 g                                               propylene carbonate                                                           cyclomethicone            1.6 g                                               ______________________________________                                    

The aqueous phase was dispersed in the oily phase at 80° C. by stirringvigorously for 5 minutes and then, the mixture was slowly cooled to 25°C.

B) The multiple emulsion was prepared in the following manner:

The primary emulsion obtained in a) was then dispersed in the followingaqueous phase called the external aqueous phase by mixing gently atambient temperature:

    ______________________________________                                        polyglyceryl methacrylate/propylene glycol                                                             15.0 g                                               acrylates/C10-30 alkyl acrylate crosspolymer                                                           0.6 g                                                carbomer 980             0.03 g                                               tetrasodium EDTA         0.054 g                                              methylparaben            0.216 g                                              imidazolidinyl urea      0.216 g                                              sodium hydroxide         0.125 g                                              water                    s.q.f. 100.0 g                                       ______________________________________                                    

EXAMPLE 3

A) A primary water/oil emulsion was prepared in the following manner:

The following aqueous phase called the internal aqueous phase was heatedto 80° C.:

    ______________________________________                                        demineralized water    26.52 g                                                methylparaben          0.1 g                                                  magnesium sulfate      0.28 g                                                 glycerine 30° B 0.8 g                                                  0-cymen-5-ol           0.04 g                                                 ______________________________________                                    

The following oily phase was heated separately to 80° C.:

    ______________________________________                                        gylceryl isostearate      2.0 g                                               polyethoxylated hydrogenated ricin oil                                                                  0.2 g                                               (7 moles)                                                                     capric/caprylic triglycerides                                                                           8.2 g                                               propylparaben             0.06 g                                              volatile silicone oil     1.6 g                                               ______________________________________                                    

The aqueous phase was dispersed in the oily phase at 80° C. by stirringvigorously for 5 minutes and then, the mixture was slowly cooled to 25°C.

B) The multiple emulsion was prepared in the following manner:

    ______________________________________                                        demineralized water  s.q.f. 100.0 g                                           Lubragel MS ®    15.0 g                                                   Pemulen TR1 ®    0.6 g                                                    Carbopol 980 ®   0.03 g                                                   hafnia biolysate     0.03 g                                                   tetrasodium EDTA     0.054 g                                                  methylparaben        0.216 g                                                  imidazolidinyl urea  0.216 g                                                  pure soda            0.125 g                                                  perfume              0.2 g                                                    ______________________________________                                    

EXAMPLE 4

The product of Example 4 was prepared by the same process of Example 3,incorporating as active ingredients 3.2 g of water-soluble sun filtersin the primary water/oil emulsion in place of the palmitate of vitamin Aand 2.8 g of liposoluble sun filters in the preparation of the multipleemulsion in place of the hafnia biolysate.

EXAMPLE 5 Triple W/O/W emulsion

The following primary W/O emulsion was prepared which was then slowlycooled to ambient temperature:

    ______________________________________                                        glyceryl isostearate       2.0 g                                              70E polyoxyethylene hydrogenated ricin oil                                                               0.2 g                                              caprylic/capric triglycerides                                                                            8.2 g                                              propyl p-hydroxybenzoate   0.06 g                                             volatile silicone oil      1.6 g                                              palmitate of vitamin A at 1.7 M UI/g                                                                     0.12 g                                             demineralized water        26.52 g                                            methyl p-hydroxybenzoate   0.1 g                                              magnesium sulfate          0.28 g                                             glycerine 30° codex 0.8 g                                              0-cymen 5-ol               0.04 g                                             ______________________________________                                    

The multiple emulsion was then obtained by slowly dispersing the primaryemulsion in the following aqueous phase at ambient temperature:

    ______________________________________                                        Lubragel MS ®     15.0 g                                                  carboxyvinylic polymer                                                                              0.03 g                                                  tetrasodium EDTA      0.054 g                                                 methyl p-hydroxybenzoate                                                                            0.216 g                                                 imidazolidinyl urea   0.216 g                                                 pure sodium hydroxide 0.125 g                                                 hafnia biolysate      0.02 g                                                  demineralized water   s.q.f. 100.0 g                                          ______________________________________                                    

EXAMPLE 6

The product of Example 6 was prepared by the process of Example 3,incorporating as active ingredient 6 g of hydrated sodium lactate inplace of the hafnia biolysate. In this way, several types of activeingredients were incorporated in a multiple emulsion according topreparations indicated above in Examples 3 to 6, and as summarized inthe following table:

    ______________________________________                                        Internal aqueous                                                                            Oily       External aqueous                                     phase         phase      phase                                                ______________________________________                                        3   Hafnia biolysate                                                                            --         --                                               4   Hydrosoluble  Liposoluble                                                                              --                                                   sun filter    sun filter                                                  5   --            Palmitate of                                                                             --                                                                 vitamin A                                                   6   Hydrating     --         --                                                   sodium lactate                                                            ______________________________________                                    

EXAMPLE 7

A) A primary water/oil emulsion was prepared in the following manner:

    ______________________________________                                        demineralized water        35.5 g                                             methylparaben              0.1 g                                              magnesium sulfate          0.28 g                                             Glycerine 30° B     2.0 g                                              0-cymen-5-ol               0.04 g                                             extract of Klebsellia pneumoniae biolysate                                                               0.005 g                                            The following oily phase was heated                                           separately to 80° C.:                                                  glyceryl isostearate       2 g                                                ketyl dimethicone copolyol (ABIL EM 90 ®)                                                            0.4 g                                              triglycerides 5545         1.0 g                                              volatile silicone oil      2.0 g                                              borage oil                 2.0 g                                              ______________________________________                                    

The aqueous phase was dispersed in the oily phase at 80° C. by stirringvigorously for 5 minutes and then, the mixture was slowly cooled to 25°C.

B) The multiple emulsion was prepared in the following manner:

The primary emulsion obtained in a) was dispersed in the followingaqueous phase called the external aqueous phase by mixing gently atambient temperature:

    ______________________________________                                        lubragel MS (R)         8 g                                                   modified hydroxyethyl cellulose                                               (AMERCEL HM 1500 ®R)                                                                              0.6 g                                                 tetrasodium EDTA        0.054 g                                               methylparaben           0.216 g                                               imidazolidinyl urea     0.125 g                                               perfume                 0.2 g                                                 glycolic extract of Mexican mimosa                                                                    5.0 g                                                 demineralized water     s.q.f. 100 g                                          ______________________________________                                    

CLINICAL STUDY

I--Test for innocuousness and measurement of sun protection factor

1--Protocol:

a) Primary cutaneous irritation

The product studied was applied as is in an occlusive buffer onto thenormal and incised flanks of 6 rabbits at a dose of 0.5 ml according tothe following protocol:

The fur of 6 rabbits was shaved 24 hours before the test on the back andflanks; and using a vaccinator, 3 parallel scarifications (about 3 cmlong, spaced 0.5 cm apart were produced on the right flank of eachanimal. The other flank was kept intact and the product was deposited on2 square pieces of Codex hydrophilic gauze with 8 thicknesses of 2.5 cmper side. One piece of gauze was applied to each of the flanks and a 10cm wide expandable band was wrapped around the trunk of the animal. Therabbits were put back in their cage for 24 hours at the end of which thebandage and the 2 pieces of gauze were removed.

b) Ocular irritation

After having verified that the 6 rabbits had healthy eyes with nodefects, the product was dropped as is at a rate of 0.1 ml into theaverted lower eyelid of the right eye of each rabbit. The eyelids werekept closed for about 10 seconds to avoid the loss of the product and toimprove contact. After holding in place for an hour, the animals wereplaced in their individual cages.

2--Results:

a) Primary cutaneous irritation

Under the experimental conditions, the product of Example 4 applied asis onto the skin caused the appearance of a slight irritation reaction(erythema) on the intact and scarified skin respectively of 3 to 6animals. These phenomena appeared to be almost totally reversible 48hours later. No notable structural modification was observed. Theprimary cutaneous irritation factor calculated according to the officialmethod was equal to 0.5. This factor leads the product of Example 4 tobe classified in the substances which do not irritate the skin.

b) Ocular irritation

Under the experimental conditions used for dropping the product ofExample 4 as is in the eye, it caused the appearance of a slightirritation reaction localized at the level of the conjunctiva of 6animals (enanthema, chemosis and profuse weeping) and the iris of 4animals (congestion). These phenomena appeared to be reversible after 24hours for the iris and after 72 hours for the conjunctiva.

The maximum ocular irritation factor (Ma0I) was obtained 1 hour afterdropping in the eye and was equal to 15.3. The average ocular irritationfactors were respectively: 3.7 after 24 hours, 1 after 48 hours and 0from 72 hours onwards. These factors lead to the product of Example 4being classified in the substances which were very slightly irritatingto the eye. By comparison, the result for a cream without an emulsifiercontaining the same sun filters at the same doses was 1.2, slightlyirritating for primary cutaneous irritation and very slightly irritatingfor ocular irritation.

CONCLUSION

The multiple emulsion therefore appears particularly well tolerated bythe skin.

II--Test for measuring the sun protection factor.

1--Experimental protocol:

Determination of the UVB Radiation Source

The apparatus used was a 150 W xenon lamp as UVB/UVA radiation. The UVradiation was conducted through 6 optical filters fitted at their endwith two 1 mm thick fibers, WG 320 and UG 11, allowing a continuousspectrum of wavelengths between 290 and 390 nm to be obtained. Each spothad an 8 mm diameter spherical form. The energy emitted by each fiberwas regulated by means of a screen and the 6 fibers delivered energieswhose values increased according to a geometric progression at the rateof 1.25. The values displayed by the apparatus were expressed inMED/min.

Preliminary Medical Check

Before any application of product, each subject underwent a medicalcheck intended to determine his/her phototype and to verify the absenceof any dermatosis or any local therapeutic treatment.

Experimental Areas

The study of the minimum erythematous dose was carried out for eachsubject on the skin of the dorsal region. The products being tested wereapplied on the dorso-lumbar area on either side of the spinal column.

Quantities of Products Applied

The products were applied over a 35 cm² area of the skin. 2 mg of theproduct were applied per cm² of skin on the area thus defined andaccurately located.

Study of the Minimum Erythematous Dose (MED) on Unprotected Skin

The MED was studied for each of the subjects before any application ofproduct. It corresponded to the first energetic dose of UVB capable ofinducing a "non-ambiguous" erythema of the unprotected skin, coveringall or most of the irradiated area. This evaluation was made between 20and 24 hours after the exposure of the subjects to the irradiation undera "daylight" type lighting.

Actual Test

About twenty minutes after the thermal stabilization of the lamp,exposure was carried out approximately 15 minutes after application ofthe product. For each of the products, the 6 doses of UV radiationapplied were determined by a geometric progression at the rate of 1.25.20 to 24 hours after this exposure, an evaluation of the cutaneouserythema was made under a "daylight" type lighting. The first energeticdose of UVB inducing a "non-ambiguous" erythema of the protected skincovering all or most of the irradiated area was recorded.

Expression of the Results

The average protection factors were calculated from the individualprotection coefficient Qi corresponding for each subject to the ratiobetween the MED obtained on the protected skin and the MED obtained onthe unprotected skin (Schultze method). The Sun Protection Factor of theproduct was calculated by the arithmetical method and expressed by theaverage and standard deviation obtained from individual results.

As a function of the factor obtained, the product was classified in oneof the following categories:

Minimum protection for SPF's comprised between 2 and 4,

Average protection for SPF's comprised between 4 and 6,

High protection for SPF's comprised between 6 and 8,

Maximum protection for SPF's comprised between 8 and 15,

Ultra protection for SPF's higher than 15.

2--Results

Study of the MED Before Application of the Products

The apparatus delivered 6 UV radiation energies which increase accordingto a geometric progression at the rate of 1.25 and were expressed inMED/min, that is:

    E=0.66-0.82-1.02-1.28-1.60-2.00

The exposure time t1 (sec) was chosen for each of the subjects as afunction of their phototype. The energy E1 for which a clear erythemawas obtained was noted in MED/min. The initial MED D1 for each subjectwas calculated according to the formula: ##EQU1##

Evaluation of the Sun Protection Factors

As previously, the apparatus delivered 6 UV radiation energies whichincrease according to a geometric progression at the rate of 1.25 andwere expressed in MED/min, that is:

    E=0.66-0.82-1.02-1.28-1.60-2.00

Determination of the exposure time t2 (sec.) was carried out as afunction of the initial MED D1 of each subject and of the coefficient ofassumed maximum protection of the product to be tested (i.e. n). In thepresent case:

n=7 for the standard 11 for the product of Example 4.

The subject was exposed to a maximum energy of:

×D1=7×D1 for the standard 11×D1 for the product of Example 4.

For the maximum energy emitted by the lamp being fixed at 2 MED/min toobtain n×D1, the following exposure time was required: ##EQU2## that was210 D1 sec. for the standard that was 330 D1 sec. for the product ofExample 4.

The energy E2 with which a clear erythema was obtained was noted inMED/min. The MED D2 after application of the products for each subjectwas calculated according to the formula: ##EQU3##

The approximate sun protection factor was calculated in the followingmanner: ##EQU4##

Under the test conditions, the approximate average sun protection factorof the standard defined by FDA was equal to: 3.4±0.8. The test wasvalidated since the sun protection coefficient obtained with thestandard was situated within the limits accepted for the method (between3.1 and 5.3). The average sun protection factor of the product ofExample 4, tested under the same conditions was equal to: 6.4±0.9. Thissame sun protection factor was determined for the product of Example 4,2 hours after application, to test the residual existence of theproduct. Under these conditions the sun protection factor was equal to:6.1±1.2

CONCLUSION

These results therefore showed the effectiveness in terms of sunprotection of the product of Example 4. The test for innocuousnessdescribed above was carried out for the product of Example 4 and thisproduct was classified as very slightly irritating for ocular irritationand as non-irritating for primary cutaneous irritation which is anexcellent result relative to a standard sun protection product. The sunprotection factor measured was comparable to that obtained with astandard emulsion containing the same filters at the same dose.

B--Test for comedolytic activity

The animal chosen for the test for comedolytic activity was the femaleHairless Rhino (hr rh) mouse, this choice being due to the fact that theskin of such an animal has a high density of comedones of large diameterand with a narrow orifice. The use of comedolytic agents on the skin ofthe animal caused the opening of the orifice of the comedo, the releaseof the keratic substance and the sebum that it contains. Two groups weremade up, each group containing 6 mice which were 6 weeks old at thestart of the test and weighing on average 18 grams each. The first groupwas made up of mice treated with distilled water (negative controlgroup), the second group was made up of mice treated with the productbeing studied. Such a treatment consisted of a topical application ofthe product studied on the interscapular area at a dose of 0.02 ml, 5days out of 7 for 21 days.

The animals were sacrificed at the end of the three weeks of treatment,24 hours after the last application. Biopsies of the skin were thentaken from the treated areas of the animals and from these biopsies,sections were prepared with a view to a standard morphometric studycarried out by methods known to one skilled in the art. The followingparameters were measured:

    ______________________________________                                        diameter of the opening of the comedo                                                               that is d                                               at the surface                                                                diameter of the comedo                                                                              that is D                                               comedonian profile    that is R = d/D                                         ______________________________________                                    

The ratio R=d/D allowed the action of the comedolytic agents to bequantified. The percentage of inhibition of the comedones was calculatedfor the product being studied relative to the negative control, that isthe following ratio: ##EQU5##

The test for keratolytic activity described above was carried out forthe product of Example 5 and the product of Example 5 was compared withtwo preparations also containing vitamin A, that is a water-siliconeemulsion and an emulsion with two phases prepared as indicatedhereafter. Thus, for the product of Example 5, 53% of the keratolyticactivity of acid vitamin A (Alberel gel) used as the standard wasobtained, while with the water/silicone emulsion 20% was obtained, andwith the two-phase emulsion 39% was obtained. The results clearly showthe advantage of the preparation of the invention illustrated by Example5 on standard preparations.

Preparation of the Products Used in the Clinical Study

    ______________________________________                                        Two-phase           The following emulsion                                    emulsion            was prepared:                                             ______________________________________                                        stearylic alcohol   1.0 g                                                     ketylic alcohol     2.0 g                                                     ketearyl octanoate  4.0 g                                                     polysorbate 60      4.0 g                                                     sorbitan stearate   4.0 g                                                     caprylic/capric triglycerides                                                                     3.0 g                                                     karite butter       3.0 g                                                     oleyl acetate (anti-lipase)                                                                       2.0 g                                                     silicone oil        0.5 g                                                     tocopherols         0.05 g                                                    demineralized water s.q.f. 100.0 g                                            carboxyvinylic polymer                                                                            0.3 g                                                     preservatives       0.7 g                                                     Lubragel MS         5.0 g                                                     palmitate of vitamin A 1.7 M UI/g                                                                 0.12 g                                                    sodium hydroxide 10%                                                                              0.3 g                                                     perfume             0.2 g                                                     hafnia biolysate    0.02 g                                                    ______________________________________                                    

Water/Silicon Emulsion

The following emulsion was prepared at 60° C.:

    ______________________________________                                        demineralized water     s.q.f. 100.22 g                                       sodium chloride         0.8 g                                                 pure citric acid        0.01 g                                                methylparaben           0.25 g                                                preservatives           2.0 g                                                 hafnia biolysate        0.02 g                                                isoketyl stearate       3.0 g                                                 arlacel 83              0.8 g                                                 hydrogenated ricin oil  0.3 g                                                 elfacos ST 9 ®      2.0 g                                                 oleyl acetate (anti-lipase)                                                                           2.0 g                                                 propylparaben           0.15 g                                                silicon DC 3225 ®   9.0 g                                                 volatile silicone       4.0 g                                                 bronopol                0.05 g                                                palmitate of vitamin A 1.7 M UI/g                                                                     0.12 g                                                perfume                 0.3 g                                                 ______________________________________                                    

Various modifications of the compositions and method of the inventionmay be made without departing from the spirit or scope thereof and it isto be understood that the invention is intended to be limited as definedin the appended claims.

What is claimed is:
 1. A multiple emulsion to administer at least onewater-soluble or liposoluble ingredient in the form of a water/oil/wateremulsion consisting essentially of a dispersed phase of a water/oil andan aqueous dispersion medium which is a gelled aqueous phase, theaqueous dispersion phase contains a gelling agent comprised of apolyglyceryl methacrylate solution, carbomers and modified carbomers,the polyglyceryl methacrylate being 5 to 15% by weight of the totalcomposition.
 2. A multiple emulsion of claim 1 wherein the aqueous phaseof the water/oil emulsion and/or the aqueous dispersion phase containsat least one water-soluble active ingredient.
 3. A multiple emulsion ofclaim 2 wherein the water soluble active ingredient is selected from thegroup consisting of sodium lactate, hafnia biolysate extracts,Klebsellia pneumonia biolysate extracts and water soluble sun filters.4. A multiple emulsion of claim 1 comprising 20 to 30% by weight of theinternal aqueous phase, 10 to 20% by weight of oil phase and 50 to 60%by weight of the aqueous dispersion phase, based on the weight of thetotal composition.